fulvestrant, palbociclib and erdafitinib in er+/her2-/fgfr-amplified metastatic breast cancer

Conditions: Metastatic Breast Cancer

Summary: this is an open-label, multi-institution, phase ib trial that evaluates the safety and tolerability and preliminary anti-tumor activity of fulvestrant, palbociclib and erdafitinib in patients with er+/her2-/fgfr-amplified metastatic breast cancer.

primary objectives to determine the safety and tolerability of fulvestrant, palbociclib and erdafitinib in patients with er+/her2-/fgfr-amplified mbc. secondary objectives * to determine the anti-tumor effect of fulvestrant, palbociclib and erdafitinib in patients with er+/her2-/fgfr-amplified mbc. * pharmacokinetic assessments of erdafitinib correlative objectives * to determine the therapeutic predictive role of fgfr1-4, ccnd1-2, cdk4 and cdk6 amplifications, and rb1 and esr1 mutations on clinical outcome * to determine if the fgfr1 amplification levels is an early surrogate of response * to determine if the cfdna results at disease progression show new genomic alterations potentially associated with resistance to cdk4/6 and fgfr inhibition * to determine pharmacodynamic biomarkers of fgfr inhibition

Eligibility criteria:
inclusion criteria: * patients must be able to swallow and retain oral medication * patients must be ≥ 18 years of age * female patients of no childbearing potential must be post-menopausal. postmenopausal female subjects should be defined prior to protocol enrollment by any of the following: * participants at least 60 years of age; or * participants under 60 years of age and naturally (spontaneous, no alternative pathologic or physiological cause) amenorrhea for at least 12 months; or * medical ovarian failure confirmed by follicle-stimulating hormone (fsh) and estradiol levels in the post menopausal range per local institutional normal range; or * prior bilateral oophorectomy; or * prior radiation castration with amenorrhea for at least 6 months; or * treatment with a luteinizing hormone-releasing hormone (lh-rh) agonist (such as goserelin acetate or leuprolide acetate) is permitted for induction of ovarian suppression as long as it has been initiated at least 28 days prior to study enrollment * patients must have ecog performance status 0 - 1 * patients must have clinical stage iv or inoperable locoregional recurrent invasive mammary carcinoma that is: * er+ and/or pgr+ (≥ 1% positive stained cells) by immunohistochemistry (ihc) * her2-negative (by ihc or fish, per asco guidelines) * fgfr1 - 4 amplified * patients must have evaluable (may have either measurable or non-measurable) disease * patients must have available tissue for fgfr determination * patients must have had at least one line of therapy in the metastatic setting * current use of any of the drugs listed on the cautionary concomitant med list has to be approved by the study chair * patients must have adequate hematologic, hepatic and renal function. all laboratory tests must be obtained within 2 weeks from study drug initiation. these include: * anc ≥ 1,500/mm3 * platelet count ≥ 100,000/mm3 * hgb ≥ 9.0 g/dl * creatinine clearance ≥ 40 ml/min/1.73 m2 * sgot, sgpt ≤ 2.5 x uln if no liver metastasis present; sgot, sgpt ≤ 4 x uln if liver metastasis present * albumin ≥ 2.0 g/dl * total serum bilirubin ≤ 1.5 x uln (≤ 3 x uln or direct bilirubin ≤ 1.5 x uln if known gilbert's syndrome) * potassium within institutional normal limits * phosphorus ≤ institutional upper limit of normal exclusion criteria: * prior use of an fgfr inhibitor * more than 2 lines of chemotherapy in the metastatic setting. no limit on endocrine therapy lines. prior exposure to cdk4/6 inhibitor acceptable. * radiation therapy ≤ 2 weeks prior to study entry. patients who have received prior radiotherapy must have recovered from toxicity (≤ grade 1) induced by this treatment (except for alopecia) * prior cancer therapy (except for endocrine therapy) must have been discontinued for 1 week prior to initiation of study drugs * concurrent anti-cancer therapy other than the ones specified in the protocol is not permitted during study participation. bisphosphonates or denosumab are allowed * major surgery within 4 weeks of enrollment * herbal preparations are not allowed throughout the study, and should be discontinued 14 days prior to initiation of study treatment * any corneal or retinal abnormality likely to increase the risk of eye toxicity, such as: * current corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration * uncontrolled glaucoma despite standard of care therapy * diabetic retinopathy with macular edema * known active wet, age-related macular degeneration (amd) * known central serous retinopathy (csr) or retinal vascular occlusion (rvo) * uncontrolled intercurrent illness including, but not limited to: * malabsorption syndrome significantly affecting gastrointestinal function * ongoing or active infection requiring antibiotics/antivirals * impairment of lung function (copd \> grade 2, lung conditions requiring oxygen therapy) * symptomatic congestive heart failure * unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months * clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment \[national cancer institute -common terminology criteria for adverse events, version 4.03, grade 3\] * qtcf ≥ 480 msec on screening ekg * known history of clinically significant qt/qtc prolongation or torsades de pointes(tdp) * st depression or elevation of ≥ 1.5 mm in 2 or more leads * diarrhea of any cause ≥ ctcae grade 2 that does not resolve within a few days when adequately treated with anti-diarrhea medications * psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary * symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and be off steroids) * known history of chronic liver or chronic renal failure * poor wound healing capacity

Keywords: fgfr inhibitor er+ metastatic breast cancer cdk4/6 inhibitor endocrine therapy